CN111018918B

CN111018918B - Metal complex, intermediate, preparation method and application thereof

Info

Publication number: CN111018918B
Application number: CN201811178107.XA
Authority: CN
Inventors: 汤文军; 徐斯尧
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2018-10-10
Filing date: 2018-10-10
Publication date: 2022-10-04
Anticipated expiration: 2038-10-10
Also published as: WO2020073962A1; EP3865494A4; EP3865494A1; US20230114794A1; JP7411650B2; CN111018918A; JP2022512691A

Abstract

The invention discloses a metal complex, an intermediate, and a preparation method and application thereof. The invention provides a metal complex shown as a formula I; it can be used as catalyst for asymmetric catalytic hydrogenation reaction, and can efficiently catalyze and synthesize a series of high optical purity (ee value)>99 percent), especially can asymmetrically catalyze and hydrogenate tetra-substituted olefin amide compounds, the chiral amide is synthesized with high optical purity (ee value can reach more than 60 percent), and the ligand bearing capacity (s/c) can reach 100,000.

Description

Metal complex, intermediate, preparation method and application thereof

Technical Field

The invention relates to a metal complex, an intermediate, and a preparation method and application thereof.

Background

Since Knowles first applied chiral phosphine ligands to transition metal catalyzed asymmetric hydrogenation in 1968, tremendous developments were made in the field of asymmetric hydrogenation. In 1972, kagan reported the first asymmetric hydrogenation of enamides (h.b. Kagan, t.p. dang, j.am.chem.soc.1972, 94,6429.), since which enamides were extensively studied as an important class of hydrogenation substrates, with a series of very important results.

The asymmetric hydrogenation of tetra-substituted beta-aryl cyclic enamides is a relatively more studied and successful asymmetric hydrogenation of tetra-substituted cyclic enamides. In 1999, zhang Xumu teaches ((a) z.zhang, g.zhu, q.jiang, d.xiao, x.zhang, j.org.chem.1999,64, 1774-1775; (b) w.tang, y.chi, x.zhang, org.lett.2002,4, 1695-1698.) in the reaction of asymmetrically hydrogenated cyclic enamides with a catalytic system of Rh and Me-Pennphos, the asymmetric hydrogenation of tetra-substituted cyclic enamides was first achieved, and ee values ranging from 73% to 98% (yield 80 to 99%) were obtained, but the substrate range was very limited. Subsequently Bruneau et al (P.Dupau, C.Bruneau, P.H.Dixneuf, adv.Synth.Catal.2001,343, 331-334.) attempted also asymmetric hydrogenation of tetra-substituted cyclic enamide substrates by catalytic systems of Ru with Me-DuPhos or Me-BPE ligands, but only obtained moderate yields (60% to 95%) and enantioselectivities (73% to 98%).

Recently, riera reported (e.salomo, s.orgue, a.riera, x.verdaguer, angelw.chem. Int.ed.2016,55, 7988-7992.) that an asymmetric hydrogenation reaction catalyzed by Ir-MAXPHOX system could also achieve catalytic effects similar to Rh or Ru (formula below).

However, there is no report in the literature on asymmetric hydrogenation of tetra-substituted α, β -alkyl cyclic enamides. (in the formula, R ¹ 、R ² 、R ³ The radicals are all alkyl groups)

As can be seen from the above research progress, although some progress has been made in asymmetric hydrogenation of enamide compounds, many challenging hydrogenation substrates still have problems of unsatisfactory yield and enantioselectivity, and many difficulties still need to be broken through, which is a very challenging issue.

Disclosure of Invention

The invention aims to solve the technical problems that the existing catalyst for synthesizing chiral amide by catalytic hydrogenation of enamide is less and has low efficiency and the like, and provides a metal complex, an intermediate, a preparation method and application thereof.

The present invention solves the above technical problems by the following technical solutions.

The invention provides a metal complex shown as a formula I:

wherein R is ¹ And R ² Each independently is hydrogen, C ₁ ～C ₁₀ Alkyl of (C) ₁ ～C ₄ Alkoxy group of (C) ₃ ～C ₃₀ Cycloalkyl, halogen or C ₆ ～C ₃₀ Aryl of (a);

M ⁿ⁺ is a transition metal ion; n is 1,2 or 3 and is determined by the corresponding ion valence number of the transition metal M;

the carbons marked with x are all chiral carbons with S configuration or all chiral carbons with R configuration;

p marked by x is all S configuration chiral P or all R configuration chiral P.

In one embodiment, certain groups of the metal complex are defined as follows, and undefined groups are as described in any of the preceding embodiments:

when R is ¹ Or R ² Each independently is C ₁ ～C ₁₀ Alkyl of (2), C ₁ ～C ₁₀ Alkyl of (A) is C _1-6 An alkyl group; said C _1-6 Alkyl is preferably each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl; wherein propyl is C ₃ Alkyl (including isomers such as n-propyl or isopropyl); butyl being C ₄ Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C ₅ Alkyl (including isomers, e.g. n-pentyl)<For example

>Isoamyl radical<For example

>Or neopentyl group<For example

>) (ii) a Hexyl is C ₆ Alkyl (including isomers)A body, such as n-hexyl); more preferably C _1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl).

when R is ¹ Or R ² Each independently is C ₁ ～C ₄ Alkoxy of (2), said C ₁ ～C ₄ The alkoxy group of (b) is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

when R is ¹ Or R ² Each independently is C ₃ ～C ₃₀ In the case of a cycloalkyl group of (A), said C ₃ ～C ₃₀ Cycloalkyl of (C) ₃ ～C ₈ Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

when R is ¹ Or R ² Each independently is C ₆ ～C ₃₀ Aryl of (2), said C ₆ ～C ₃₀ Aryl of is C ₆ ～C ₁₄ Aryl (e.g., phenyl or naphthyl).

when R is ¹ Or R ² When each is independently halogen, the halogen is fluorine, chlorine, bromine or iodine.

R ¹ and R ² The same is true.

the transition metal ion M ⁿ⁺ Preferably Rh ⁺ 、Ru ²⁺ 、Ni ²⁺ 、Ir ²⁺ 、Pd ²⁺ 、Cu ²⁺ 、 Pt ²⁺ 、Co ²⁺ Or Au ³⁺ (ii) a Preferably Ru ²⁺ Or Rh ⁺ 。

the anion R ^- Is an anion which may be conventional in the art, e.g. BF ₄ ^- 、SbF ₆ ^- 、TfO ^- 、 B(C ₆ H ₅ ) ₄ ^- 、B[3,5-(CF ₃ ) ₂ C ₆ H ₃ ] ₄ ^- Or PF ₆ ^- (ii) a Preferably BF ₄ ^- Or PF ₆ ^- 。

the metal complex is

Certain groups of the metal complexes are defined below, with undefined groups as in any of the preceding schemes:

the metal complex is

In one embodiment, the metal complex is

At a certain positionIn the technical scheme, the metal complex is

The invention also provides a preparation method of the metal complex, which comprises the following steps: in an inert gas atmosphere, in a first organic solvent, carrying out a complexation reaction shown in the following formula on a transition metal precursor shown in a formula III and a ligand compound shown in a formula II to obtain the metal complex;

wherein R is ¹ 、R ² 、M ⁿ⁺ 、R ^- N and ". Sup." are as defined above.

In the preparation method of the metal complex, the operation and conditions of the complexation reaction may be those conventional in the art.

The inert gas may be an inert gas conventional in the art for such reactions, such as argon and/or nitrogen, among others.

Wherein the first organic solvent may be one or more of organic solvents conventional in such reactions in the art, such as ether solvents (e.g., one or more of tetrahydrofuran, diethyl ether and methyl tert-butyl ether MTBE), nitrile solvents (e.g., acetonitrile), alkyl halide solvents (e.g., one or more of dichloromethane, 1,2-dichloroethane and chloroform), sulfoxide solvents (e.g., dimethylsulfoxide DMSO) and amide solvents (e.g., N-dimethylformamide DMF), preferably tetrahydrofuran.

The amount of the first organic solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

Wherein the molar ratio of the transition metal precursor III to the ligand compound II may be a molar ratio conventional in such reactions in the art, and the molar ratio of the transition metal precursor III to the ligand compound II is preferably 1.0 to 1.3 (e.g. 1.

The temperature of the complexation reaction may be, among others, a temperature conventional in such reactions in the art, e.g., -15 ℃ to 30 ℃ (e.g., 0 ℃ to 25 ℃).

Wherein, the progress of the complexation reaction can be monitored by TLC or HPLC, and is generally used as the end point of the reaction when the transition metal precursor shown in formula III or the ligand compound shown in formula II disappears. The reaction time may be 0.1 to 1 hour (e.g., 0.1 to 0.5 hour).

Wherein the reaction further comprises a post-treatment step, which may comprise the following operations: concentrating, washing, and removing solvent. The concentration may be carried out using rotary evaporation and the washing may be carried out using diethyl ether, for example 1 wash; the washed solvent can be directly poured out after the solid is separated out, and the residual solvent can be pumped by an oil pump or directly filtered.

The preparation method of the metal complex can further comprise the following steps: in an inert gas atmosphere, in a second organic solvent, carrying out a reduction reaction shown in the following formula on a compound shown in the formula IV and a reducing agent to obtain a compound II;

wherein R is ¹ And R ² The definitions of (A) and (B) are as described above.

The operation and conditions of the reduction reaction can be those conventional in the art, and the following conditions are particularly selected in the present invention:

in the reduction reaction, the inert gas may be an inert gas conventional in the art for such reactions, such as argon and/or nitrogen.

In the reduction reaction, the second organic solvent may be an organic solvent conventional in the reactions of this type in the art, such as one or more of an ethereal solvent (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether, and methyl tert-butyl ether MTBE), an aromatic solvent (e.g., toluene and/or benzene), a nitrile solvent (e.g., acetonitrile), an alkyl halide solvent (e.g., one or more of dichloromethane, 1,2-dichloroethane, and chloroform), a sulfoxide solvent (e.g., dimethylsulfoxide DMSO), and an amide solvent (e.g., N-dimethylformamide DMF), preferably toluene and/or tetrahydrofuran.

The amount of the second organic solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

In the reduction reaction, the reducing agent may be a reducing agent conventional in the reactions of this type in the art, such as one or more of triethylamine, diisopropylethylamine, tri-n-butylamine, and 1,4-diazabicyclo [2.2.2] octane; preferably triethylamine and/or 1,4-diazabicyclo [2.2.2] octane.

In the reduction reaction, the molar ratio of the reducing agent to the compound IV may be a molar ratio conventional in the reactions of the type in the art, and the molar ratio of the reducing agent to the compound IV is preferably 10 to 1:1 (e.g., 3:1).

In the reduction reaction, the temperature of the reaction may be a temperature conventional in the art, for example, from 20 ℃ to 100 ℃ (e.g., from 60 ℃ to 80 ℃).

In the reduction reaction, the progress of the reaction can be monitored by TLC or HPLC, and the end point of the reaction is generally determined when the compound represented by the formula IV disappears. The reaction time may be 4 to 24 hours (e.g., 12 to 16 hours).

The preparation method of the metal complex can further comprise the following steps: in an inert gas atmosphere, in a third organic solvent, in the presence of alkali, a ligand and a metal oxidant, carrying out dimerization coupling reaction on a compound shown as a formula V and a compound shown as a formula V' as shown in the specification to obtain a compound IV;

wherein R is ¹ And R ² The definitions of (A) and (B) are as described above; using a symbolNote that both P are S configuration chiral P or R configuration chiral P.

The operations and conditions of the coupling reaction can be those conventional in the art, and the following conditions are particularly chosen in the present invention:

in the coupling reaction, the inert gas may be an inert gas conventional in the art for such reactions, such as argon and/or nitrogen.

In the coupling reaction, the third organic solvent may be one or more of organic solvents conventional in such reactions in the art, such as ethereal solvents (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether, and methyl tert-butyl ether MTBE), aromatic solvents (e.g., toluene and/or benzene), nitrile solvents (e.g., acetonitrile), halogenated alkane solvents (e.g., one or more of dichloromethane, 1,2-dichloroethane, and chloroform), sulfoxide solvents (e.g., dimethylsulfoxide DMSO), and amide solvents (e.g., N-dimethylformamide DMF), preferably tetrahydrofuran.

The amount of the third organic solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

In the coupling reaction, the base may be a base conventional in such reactions in the art, such as one or more of n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamine, and lithium diisopropylamine magnesium chloride lithium chloride complex; preferably lithium diisopropylamide and/or tert-butyllithium.

In the coupling reaction, the ligand can be a ligand conventional in the reactions in the field, such as one or more of Tetramethylethylenediamine (TMEDA), tetrahydrofuran (THF), hexamethylphosphoramide (HMPA), and 1,4-diazabicyclo [2,2,2] octane (DABCO); preferably Tetramethylethylenediamine (TMEDA).

In the coupling reaction, the metal oxidant may be a metal oxidant conventional in such reactions in the art, such as one or more of copper (II) chloride, iron (III) chloride, copper (II) pivalate, and copper (II) isobutyrate; preferably copper (II) chloride.

In the coupling reaction, the molar ratio of the base to the compound V may be a molar ratio conventional in such reactions in the art, and the molar ratio of the base to the compound V is preferably 10 to 1:1 (e.g., 1.5.

In the coupling reaction, the molar ratio of the ligand to the compound V may be a molar ratio conventional in this type of reaction in the art, and the molar ratio of the ligand to the compound V is preferably 10 to 1:1 (e.g. 1.5.

In the coupling reaction, the molar ratio of the metal oxidant to the compound V may be a molar ratio conventional in the art, for example, the molar ratio of the metal oxidant to the compound V is 10 to 1:1 (e.g., 3:1).

In the coupling reaction, the temperature of the reaction may be a temperature conventional in this type of reaction in the art, for example-78 ℃ to 30 ℃.

In the coupling reaction, the progress of the reaction can be monitored by TLC or HPLC, and is generally determined as the end point of the reaction when the compound of formula V disappears.

The preparation method of the metal complex can further comprise the following steps: in an inert gas atmosphere, in a fourth organic solvent and in the presence of a reducing agent and borane, carrying out reduction and oxidation reactions shown in the following steps on a compound shown in a formula VI to obtain a compound V;

wherein R is ¹ Is as defined above; p marked by x is S configuration chiral P or R configuration chiral P.

The operation and conditions of the reduction and oxidation reactions can be those conventional in the art, and the following conditions are particularly selected in the present invention:

in the reduction and oxidation reactions, the inert gas may be an inert gas conventional in the art for such reactions, such as argon and/or nitrogen.

In the reduction and oxidation reaction, the fourth organic solvent may be an organic solvent conventional in the reaction in the art, such as one or more of an ether solvent (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether, and methyl tert-butyl ether MTBE), an aromatic solvent (e.g., toluene and/or benzene), a nitrile solvent (e.g., acetonitrile), an alkyl halide solvent (e.g., one or more of dichloromethane, 1,2-dichloroethane, and chloroform), a sulfoxide solvent (e.g., dimethylsulfoxide DMSO), and an amide solvent (e.g., N-dimethylformamide DMF), preferably tetrahydrofuran and/or dioxane.

In the reduction and oxidation reaction, the amount of the fourth organic solvent may be the amount conventionally used in the reaction in the field, so as not to affect the reaction.

In the reduction and oxidation reaction, the reducing agent can be a reducing agent which is conventional in the reaction in the field, such as one or more of triethylamine, diisopropylethylamine and tri-n-butylamine, trichlorosilane and titanium tetraisopropoxide, or polymethoxyhydrosilane and titanium tetraisopropoxide; preferred are polymethoxyhydrosilanes and titanium tetraisopropoxide.

In the reduction and oxidation reaction, the molar ratio of the reducing agent to the compound VI can be a molar ratio conventional in the reactions in the field, and the molar ratio of the reducing agent to the compound VI is preferably 10 to 1:1 (e.g. 2.5.

In the reduction and oxidation reaction, the borane can be a borane which is conventional in the reactions in the field, and is preferably a borane in tetrahydrofuran solution (for example, a 1M tetrahydrofuran solution).

In the reduction and oxidation reaction, the molar ratio of the borane to the compound VI can be a molar ratio conventional in the reaction in the art, and the molar ratio of the metal oxidant to the compound VI is preferably 10 to 1:1 (e.g., 2.5.

In the reduction and oxidation reactions, the temperature of the reduction reaction may be a temperature conventional in the art, such as 20 to 80 ℃ (e.g., 55 to 70 ℃).

In the reduction and oxidation reactions, the temperature of the oxidation reaction may be a temperature conventional in the art, such as 10 to 70 ℃ (e.g., 15 to 40 ℃).

In the reduction and oxidation reactions, the progress of the reactions can be monitored by TLC or HPLC, and the end point of the reactions is generally determined when the compound represented by formula VI disappears and the reduced product V is formed. The reduction reaction time is 2 to 24 hours (e.g., 4 to 24 hours). The oxidation reaction time is 1 to 24 hours (e.g., 2 to 24 hours).

The preparation method of the metal complex can further comprise the following steps: in a solvent, in the presence of an oxidation reagent, carrying out an oxidation reaction shown as the following on a compound shown as a formula VII to obtain a compound VI;

The operation and conditions of the oxidation reaction can be those conventional in the art, and the following conditions are particularly selected in the present invention:

in the oxidation reaction, the solvent may be one or more of a solvent which is conventional in such reactions in the art, such as water, an alcohol solvent (e.g., methanol), an ether solvent (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether, MTBE), an aromatic solvent (e.g., toluene and/or benzene), a nitrile solvent (e.g., acetonitrile), a haloalkane solvent (e.g., one or more of dichloromethane, 1,2-dichloroethane and chloroform), a sulfoxide solvent (e.g., dimethylsulfoxide, DMSO) and an amide solvent (e.g., N-dimethylformamide, DMF), preferably water and methanol.

The amount of the solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

In the oxidation reaction, the oxidizing agent can be an oxidizing agent conventional in the reactions in the field, such as hydrogen peroxide and/or m-chloroperoxybenzoic acid, and preferably hydrogen peroxide.

In the oxidation reaction, the molar ratio of the oxidizing reagent to the compound VII may be a molar ratio conventional in the reactions in the art, and the molar ratio of the oxidizing reagent to the compound VII is preferably 1 to 1:1 (e.g., 1:2 to 1.87.

In the oxidation reaction, the temperature of the reduction reaction may be a temperature conventional in the art for such reactions, for example, 0 to 80 ℃, preferably 15 to 40 ℃ (for example, 30 ℃).

In the oxidation reaction, the progress of the reaction can be monitored by TLC or HPLC, and is generally defined as the end point of the reaction when the compound represented by formula VII disappears.

The preparation method of the metal complex can further comprise the following steps: carrying out chiral separation on a compound VII' to obtain the compound VII;

wherein R is ¹ Is as defined above; p marked by x in the compound VII is chiral P with S configuration or chiral P with R configuration.

The procedures and conditions for the chiral separation may be those conventional in the art.

In the present invention, it is preferable to prepare a column type: CHIRALPAK AD-H, particle Size =5 μm; dimensions =4.6mm 250mm; mobile phase: isopropanol/n-hexane =5/95, flow rate: 1ml per minute; detection wavelength: 210nm.

The preparation method of the metal complex can also comprise the following steps: in an inert gas atmosphere, in a fifth organic solvent and in the presence of a reducing reagent and sulfur, carrying out reduction and vulcanization reactions shown in the specification on a compound shown in a formula VI 'to obtain a compound VII';

wherein R is ¹ Is as defined above.

The operations and conditions of the reduction and sulfidation reactions can be those conventional in the art, and the following conditions are specifically selected for the present invention:

in the reduction and sulfidation reactions, the inert gas may be an inert gas conventional in the art for such reactions, such as argon and/or nitrogen.

In the reduction and sulfurization reaction, the fifth organic solvent may be an organic solvent conventional in the reactions of this type in the art, such as one or more of an ethereal solvent (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether MTBE), an aromatic solvent (e.g., toluene and/or benzene), a nitrile solvent (e.g., acetonitrile), a halogenated alkane solvent (e.g., one or more of dichloromethane, 1,2-dichloroethane and chloroform), a sulfoxide solvent (e.g., dimethylsulfoxide DMSO) and an amide solvent (e.g., N-dimethylformamide DMF), preferably tetrahydrofuran and/or dioxane.

The amount of the fifth organic solvent may be conventional in the art for such reactions, so as not to affect the reaction.

In the reduction and sulfurization reaction, the reducing agent can be a reducing agent which is conventional in the reaction in the field, such as one or more of triethylamine, diisopropylethylamine and tri-n-butylamine, trichlorosilane and titanium tetraisopropoxide, or polymethoxyhydrosilane and titanium tetraisopropoxide; preferred are polymethoxyhydrosilanes and titanium tetraisopropoxide.

In the reduction and sulfidation reaction, the molar ratio of the reducing agent to the compound VI 'may be a molar ratio conventional in the art in such reactions, and the molar ratio of the reducing agent to the compound VI' is preferably 10 to 1:1 (e.g., 2.5 to 1.4.

In the reduction and sulfurization reaction, the sulfur can be the sulfur conventional in the reaction in the field, such as sulfur powder.

In the reduction and sulfidation reaction, the molar ratio of the sulfur to the compound VI 'may be a molar ratio conventional in the art in such reactions, and the molar ratio of the sulfur to the compound VI' is preferably 10 to 2:1 (e.g., 2.5.

In the reduction and sulfidation reactions, the temperature of the reduction reaction may be a temperature conventional in the art for such reactions, such as 20 to 80 ℃ (e.g., 55 to 70 ℃).

In the reduction and sulfurization reaction, the progress of the reaction can be monitored by TLC or HPLC, and is generally defined as the end point of the reaction when the compound represented by the formula VI' disappears. The reduction reaction time is 2 to 24 hours (e.g., 4 to 24 hours).

The preparation method of the metal complex can further comprise the following steps: in a sixth organic solvent, in the presence of a reducing agent, carrying out a reductive hydrogenation reaction shown as the following on a compound shown as a formula VIII to obtain a compound VI';

wherein R is ¹ Is as defined above.

in the reduction reaction, the sixth organic solvent may be one or more of organic solvents conventional in such reactions in the art, such as ester solvents (e.g., ethyl acetate), ether solvents (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether, and methyl tert-butyl ether MTBE), aromatic solvents (e.g., toluene and/or benzene), nitrile solvents (e.g., acetonitrile), halogenated alkane solvents (e.g., one or more of dichloromethane, 1,2-dichloroethane, and chloroform), sulfoxide solvents (e.g., dimethyl sulfoxide DMSO), and amide solvents (e.g., N-dimethylformamide DMF), preferably ethyl acetate.

The amount of the sixth organic solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

In the reduction reaction, the reducing agent may be a reducing agent conventional in such reactions in the art, such as a palladium catalyst and hydrogen; such as palladium on carbon and/or palladium hydroxide on carbon (e.g., 10% palladium on carbon).

The hydrogen pressure in the reduction reaction can be argon as is conventional in the art for such reactions, e.g., 15 to 750psi (e.g., 30 to 500 psi).

In the reduction reaction, the temperature of the reduction reaction may be a temperature conventional in this type of reaction in the art, for example, 40 ℃.

In the reduction reaction, the progress of the reaction can be monitored by TLC or HPLC, and the end point of the reaction is generally determined when the compound represented by the formula VIII disappears.

The preparation method of the metal complex can further comprise the following steps: in a seventh organic solvent, in the presence of a brominating reagent and alkali, carrying out bromination and cyclization reactions on a compound shown as a formula IX as shown in the specification to obtain a compound VIII;

wherein R is ¹ Is as defined above.

The operations and conditions of the bromination, cyclization reaction can be those conventional in the art, and the following conditions are particularly selected in the present invention:

in the bromination, cyclization reaction, the seventh organic solvent may be an organic solvent conventional in such reactions in the art, such as one or more of an ether solvent (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether MTBE), an aromatic solvent (e.g., toluene and/or benzene), a nitrile solvent (e.g., acetonitrile), an alkyl halide solvent (e.g., one or more of dichloromethane, 1,2-dichloroethane and chloroform), a sulfoxide solvent (e.g., dimethylsulfoxide DMSO), and an amide solvent (e.g., N-dimethylformamide DMF), preferably carbon tetrachloride and tetrahydrofuran.

The seventh organic solvent may be used in an amount conventional in such reactions in the art so as not to affect the reaction.

In the bromination and cyclization reaction, the brominating reagent can be a brominating reagent which is conventional in the reactions in the field, such as liquid bromine.

In the bromination and cyclization reaction, the molar ratio of the brominating agent to the compound IX can be a molar ratio which is conventional in the reactions in the field, and the molar ratio of the brominating agent to the compound IX is preferably 10 to 1:1 (for example 2:1).

In the bromination and cyclization reaction, the base can be a base conventional in the reaction in the field, such as one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide and lithium tert-butoxide, and sodium tert-butoxide is preferred.

In the bromination and cyclization reaction, the molar ratio of the base to the compound IX may be a molar ratio conventional in the reaction in the field, and the molar ratio of the base to the compound IX is preferably 10 to 2:1 (e.g., 2:1).

In the bromination, cyclization reaction, the temperature of the bromination reaction may be a temperature conventional in the art for such reactions, e.g., 0-30 ℃.

In the bromination, cyclization reaction, the temperature of the cyclization reaction may be a temperature conventional in such reactions in the art, for example, 0 to 30 ℃.

In the bromination, cyclization reaction, the progress of the reaction can be monitored by TLC or HPLC, and is generally defined as the end point of the reaction when the compound of formula IX disappears. The reaction time is 2 to 24 hours (e.g., 4 to 24 hours).

The preparation method of the metal complex can further comprise the following steps:

step 1) in an eighth organic solvent, phosphorus trichloride and MgR ¹ Cl, vinyl groupCarrying out alkylation reaction on magnesium bromide;

step 2), reacting water with the reaction system in the step 1);

step 3) reacting alkali and formaldehyde with the reaction system in the step 2) to obtain the compound IX;

wherein R is ¹ Is as defined above.

The operations and conditions of the reaction described may be those conventional in the art, and the following conditions are particularly chosen in the present invention:

wherein, the eighth organic solvent may be one or more of organic solvents conventional in such reactions in the art, such as ether solvents (e.g., one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether MTBE), aromatic solvents (e.g., toluene and/or benzene), nitrile solvents (e.g., acetonitrile), halogenated alkane solvents (e.g., one or more of dichloromethane, 1,2-dichloroethane and chloroform), sulfoxide solvents (e.g., dimethyl sulfoxide DMSO) and amide solvents (e.g., N-dimethylformamide DMF), preferably tetrahydrofuran and/or dioxane.

The amount of the eighth organic solvent may be conventional in the art for such reactions so as not to interfere with the reaction.

Wherein, the MgR ¹ The molar ratio of Cl to said phosphorus trichloride may be that conventional in the art for such reactions, said MgR ¹ The molar ratio of Cl to phosphorus trichloride is preferably 1.2:1 to 0.8.

Wherein the molar ratio of the vinylmagnesium bromide to the phosphorus trichloride can be a molar ratio conventional in the reactions of the type in the art, and the molar ratio of the vinylmagnesium bromide to the phosphorus trichloride is preferably 1.2 to 0.8 (e.g., 1:1.

Wherein the molar ratio of said water to said phosphorus trichloride may be a molar ratio conventional in such reactions in the art, and the molar ratio of said water to said phosphorus trichloride is preferably from 10.

Wherein, the molar ratio of the formaldehyde to the phosphorus trichloride can be a molar ratio which is conventional in the reaction in the field, and the molar ratio of the formaldehyde to the phosphorus trichloride is preferably 10.

The base may be, among others, a base conventional in such reactions in the art, such as sodium hydroxide and/or potassium hydroxide.

Wherein the molar ratio of the base to the phosphorus trichloride can be a molar ratio conventional in such reactions in the art, for example the molar ratio of the base to the phosphorus trichloride is preferably from 10.

The temperature of the reaction may be, among others, a temperature conventional in such reactions in the art, such as-50 ℃ to 60 ℃ (e.g., 15 ℃ to 45 ℃).

Wherein the reaction can progress by TLC, HPLC or ³¹ P-NMR detection was monitored.

The invention also provides a compound shown as a formula II,

wherein R is ¹ 、R ² And "-" are as defined above.

In a certain embodiment of the present invention, the compound represented by formula II is any one of the following structures:

the invention also provides a compound shown as the formula IV,

wherein R is ¹ 、R ² And ". Sup." are defined as above.

In a certain embodiment of the present invention, the compound represented by formula IV is any one of the following structures:

the invention also provides a compound shown as the formula V,

wherein R is ¹ 、R ² And "-" are as defined above.

In a certain embodiment of the present invention, the compound represented by formula V has any one of the following structures:

the invention also provides a compound shown as the formula VI,

wherein R is ¹ And "-" are as defined above.

In a certain embodiment of the present invention, the compound represented by formula VI has any one of the following structures:

the invention also provides a compound shown in the formula VII,

wherein R is ¹ And "-" are as defined above.

In a certain embodiment of the present invention, the compound represented by formula VII is any of the following structures:

the invention also provides a compound shown as the formula VII',

wherein R is ¹ The definitions of (A) and (B) are as described above.

In a certain embodiment of the present invention, the compound represented by formula VII' is any of the following structures:

the invention also provides a compound shown as the formula VI',

wherein R is ¹ The definitions of (A) and (B) are as described above.

In a certain embodiment of the present invention, the compound represented by formula VI' has any one of the following structures:

the invention also provides a compound shown as the formula VIII,

wherein R is ¹ The definitions of (c) are as described above.

In a certain embodiment of the present invention, the compound represented by formula VIII has any one of the following structures:

the invention also provides a compound shown as the formula IX,

wherein R is ¹ The definitions of (c) are as described above.

In a certain embodiment of the present invention, the compound represented by formula IX has any one of the following structures:

the invention provides a preparation method of a compound II, which comprises the following steps: in an inert gas atmosphere, in a second organic solvent, carrying out a reduction reaction shown in the following formula on a compound shown in the formula IV and a reducing agent to obtain a compound II;

wherein R is ¹ And R ² The definitions of (A) and (B) are as described above.

In the preparation method of the compound II, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound IV, which comprises the following steps: in an inert gas atmosphere, in a third organic solvent, in the presence of alkali, a ligand and a metal oxidant, carrying out dimerization coupling reaction shown as the following on a compound shown as a formula V to obtain a compound IV;

wherein R is ¹ And R ² Are as defined above, and R ¹ And R ² The same; both P' S marked with x are chiral P in S configuration or chiral P in R configuration.

In the preparation method of the compound IV, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound V, which comprises the following steps: in an inert gas atmosphere, in a fourth organic solvent and in the presence of a reducing agent and borane, carrying out reduction and oxidation reactions shown in the following steps on a compound shown in a formula VI to obtain a compound V;

In the preparation method of the compound V, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound VI, which comprises the following steps: in a solvent, in the presence of an oxidation reagent, carrying out an oxidation reaction shown as the following on a compound shown as a formula VII to obtain a compound VI;

In the preparation method of the compound VI, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound VII, which comprises the following steps: carrying out chiral separation on a compound VII' to obtain the compound VII;

In the preparation method of the compound VII, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound VII', which comprises the following steps: in an inert gas atmosphere, in a fifth organic solvent and in the presence of a reducing reagent and sulfur, carrying out reduction and vulcanization reactions shown in the specification on a compound shown in a formula VI 'to obtain a compound VII';

wherein R is ¹ Is as defined above.

In the preparation method of the compound VII', the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound VI', which comprises the following steps: in a sixth organic solvent, in the presence of a reducing agent, carrying out a reductive hydrogenation reaction shown as the following on a compound shown as a formula VIII to obtain a compound VI';

wherein R is ¹ Is as defined above.

In the preparation method of the compound VI', the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound VIII, which comprises the following steps: in a seventh organic solvent, in the presence of a brominating reagent and alkali, carrying out bromination and cyclization reactions on a compound shown as a formula IX as shown in the specification to obtain a compound VIII;

wherein R is ¹ Is as defined above.

In the preparation method of the compound VIII, the operation and the conditions of the reaction are the same as those described above.

The invention provides a preparation method of a compound IX, which comprises the following steps:

step 1) in an eighth organic solvent, phosphorus trichloride and MgR ¹ Reacting Cl and vinyl magnesium bromide;

step 2), reacting water with the reaction system in the step 1);

wherein R is ¹ Is as defined above.

In the preparation method of the compound IX, the operation and the conditions of the reaction are the same as those described above.

The invention provides an application of the metal complex in asymmetric catalytic hydrogenation reaction; which comprises the following steps: in an organic solvent in the presence of a hydrogen atmosphere and said metal complex

Carrying out asymmetric hydrogenation reduction reaction on the compound A with the structure to obtain a corresponding compound B;

wherein, when the metal complex is

When the compound B is in the dominant configuration shown as B-1,

when the metal complex is

When the compound B is in the dominant configuration shown as B-2,

in the application, the metal complex is used as a catalyst.

In the application, the metal complex can be generated in situ by the transition metal precursor shown in the formula III and the ligand compound shown in the formula II.

In a certain technical scheme, the advantageous configuration has an ee value of more than 65%, preferably more than 95%; more preferably >99%.

In one embodiment, the composition comprises

Compound A of structure (la), preferably represented by formula A-1:

wherein the dotted line represents none or annulation;

said R ^a 、R ^b And R ^c Each independently is H, -COOH, -OH, -CN, optionally substituted alkyl-oxy-carbonyl, optionally substituted alkyl-carbonyl-oxy, optionally substituted alkyl or cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

or, R ^a And R ^b Together with the carbon atoms to which they are attached form an optionally substituted cycloalkene or an optionally substituted heterocycloalkene;

said R ^d Independently an optionally substituted alkyl or cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

Wherein said "optionally substituted" may be unsubstituted or substituted by a substituent conventional in the art so as not to interfere with the reaction; for example by the following groups: halogen (e.g., F, cl, br, or I), haloalkyl, -OH, -CN, alkyl-oxy, alkyl-S-, carboxy, ester, carbonyl, amide, optionally substituted aminosulfonyl, or optionally substituted phenyl; the number of said "substitution" may not be limited; when optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, the "substitution" may be the formation of a fused ring with the cycloalkene, heterocycloalkene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

In a certain embodiment, in the compound a, the alkyl is C ₁ ～C ₁₀ Alkyl (e.g. C) ₁ ～C ₆ Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl).

In one embodiment, in said compound a, said alkyl-oxy, alkyl-oxy-carbonyl and alkyl-carbonyl-oxy groups, said alkyl is independently an alkyl group as defined above.

In a certain embodiment, in the compound a, the cycloalkyl is C ₃ ～C ₃₀ Cycloalkyl (e.g. C) ₃ ～C ₈ Cycloalkyl groups such as cyclopentyl or cyclohexyl, for example).

In one embodiment, in the compound a, the heterocyclic hydrocarbon group is "a 4-to 7-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O and S" (e.g., "a 5-to 6-membered heterocycloalkyl group having 1 to 2 heteroatoms selected from N and/or O").

In a certain embodiment, in the compound a, the aryl is C ₆ ～C ₁₄ Aryl (e.g., phenyl).

In one embodiment, in the compound A, the heteroAryl is one or more of heteroatom selected from N, O and S, and C with 1-4 heteroatom ₁ ～C ₁₀ Heteroaryl "(for example," heteroatom is selected from N, C with 1-2 heteroatoms) ₃ ～C ₉ Heteroaryl ").

In a certain embodiment, in the compound a, the cyclic olefin is C ₅ ～C ₇ Cycloalkanes of (e.g. cyclopentene or cyclohexene).

In one embodiment, in the compound a, the heterocyclic olefin is a 5-to 7-membered heterocyclic olefin having 1 to 2 heteroatoms selected from N, O and S.

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: said R ^a 、R ^b Or R ^c When it is an optionally substituted alkyl group, said optionally substituted alkyl group is C ₁ ～C ₆ Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl, and also methyl.

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: said R ^a 、R ^b Or R ^c is-COOH or optionally substituted alkyl-oxy-carbonyl, preferably C ₁ ～C ₆ Alkyl-oxy-carbonyl (e.g., methyl-oxy-carbonyl).

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: said R ^a 、R ^b Or R ^c When optionally substituted aryl, the optionally substituted aryl is phenyl or halo-substituted phenyl (e.g., bromophenyl)

)。

In one embodiment, the combination isCertain groups of object a are defined below, with undefined groups as described in any of the preceding schemes: said "R" is ^a And R ^b When taken together with the carbon atom to which it is attached to form an optionally substituted cycloalkene, the "optionally substituted cycloalkene" is a benzocycloalkene (e.g., a benzocycloalkene

) Or cyclohexene.

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: r is ^d When it is an optionally substituted alkyl group, said optionally substituted alkyl group is C ₁ ～C ₆ An alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl, again for example methyl).

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: r is ^d Is methyl, and R ^b Is an optionally substituted aryl group; namely the alpha-aryl amide compound,

in one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: r ^d Independently is methyl, and R ^b Is optionally substituted alkyl-oxy-carbonyl; namely the alpha-dehydroamino acid derivative

In one embodiment, certain groups of compound a are defined as follows, and undefined groups are as described in any of the preceding embodiments: r ^d Independently is methyl, R ^a Or R ^c Each independently is optionally substituted alkyl-oxy-carbonyl; namely beta- (acetylamino) acrylate

The use of the metal complexes in catalytic hydrogenation, wherein the compounds A and correspondingly the compounds B-1 can be selected from the following compounds:

said compound a and correspondingly compound B-2 may be selected from the following compounds:

the use of the metal complex in catalytic hydrogenation wherein the organic solvent may be one or more of solvents conventional in such reactions in the art, such as ester solvents (e.g. ethyl acetate), ethereal solvents (e.g. one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether, MTBE), aromatic solvents (e.g. toluene and/or benzene), nitrile solvents (e.g. acetonitrile), haloalkane solvents (e.g. one or more of dichloromethane, 1,2-dichloroethane and chloroform), sulfoxide solvents (e.g. dimethylsulfoxide, DMSO) and amide solvents (e.g. N, N-dimethylformamide, DMF), preferably ethyl acetate.

The amount of the organic solvent may be an amount conventionally used in such reactions in the art so as not to affect the reaction.

Wherein, the molar ratio of the compound a to the metal complex can be a molar ratio which is conventional in the reactions of this type in the field, and is preferably 100:1 to 100,000 (e.g., 200.

The hydrogen pressure may be, among others, a pressure conventional in such reactions in the art, such as 750 psi.

The temperature of the reduction reaction may be, among others, a temperature conventional in such reactions in the art, for example, 20 to 100 ℃ (e.g., 20 to 80 ℃, further e.g., 50 ℃).

Wherein the progress of the reaction can be monitored by TLC, HPLC, LC-MS or GC-MS, and the end point of the reaction is usually determined when the substrate disappears. The reaction time may be 4 to 24 hours (e.g., 12 to 18 hours).

In the application, after the reduction reaction is finished, the method may further include a post-treatment step, and the post-treatment step may include the following operations: removing hydrogen, filtering, washing, concentrating, and removing solvent. The filtration can be performed by using a microporous filter membrane to remove metal ions; the washing can be carried out by using water and a saturated sodium chloride solution in sequence; the concentration can be carried out by rotary evaporation; the solvent removal can be carried out by means of oil pump drainage.

In the present invention, the room temperature may be defined as a room temperature which is conventional in the art, and is preferably 5 to 30 ℃.

Radical definitions

In the present invention, "C ₁ ～C ₁₀ The "alkyl group" of (a) represents a straight-chain or branched saturated aliphatic hydrocarbon group having up to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, isoheptyl, octyl and isooctyl.

In the present invention, the term "C ₁ -C ₆ Alkyl "is preferably each independently methyl, ethyl, propyl, butyl, pentyl or hexyl; wherein propyl is C ₃ Alkyl (including isomers such as n-propyl or isopropyl); the butyl radical being C ₄ Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C ₅ Alkyl (including isomers, e.g. n-pentyl)<For example

>Isoamyl radical<For example

>Or neopentyl group<For example, in

>) (ii) a Hexyl is C ₆ Alkyl (including isomers, such as n-hexyl);

in the present invention, the term "C ₁ -C ₄ Alkyl groups "are preferably each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

Similarly, "C ₁ ～C ₁₀ Alkoxy of "or" C ₁ ～C ₁₀ The "alkyl-oxy group" of (b) represents an alkyl group as defined above, which is bonded through an oxygen atom, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

In the present invention, halogen includes F, cl, br or I.

In the present invention, "aryl" represents a substituent having the property of an aromatic ring structure, such as C ₆ -C ₃₀ Aryl groups useful in the present invention include, but are not limited to: phenyl, naphthyl, anthracyl, and the like. In the present invention, the aryl group includes an unsubstituted or substituted aryl group, wherein substituted means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of: c ₁ ～C ₄ Alkyl radical, C ₃ ～C ₁₀ Cycloalkyl, halogen, hydroxy, carboxyl, aldehyde, acyl, amino, -NR ³ R ⁴ Wherein R is ³ And R ⁴ Each is H or C ₁ -C ₄ Alkyl or C ₁ -C ₄ A haloalkyl group of (a). Representative aryl groups include aryl groups bearing electron donating and/or electron withdrawing substituents, such as p-tolyl, p-methoxyphenyl, p-chlorophenyl, and the like. Similarly, "arylalkyl" refers to a substituent group to which an aryl group and an alkyl group are attached, such as phenylmethyl, phenylethyl, phenylpropyl, and the like.

Similarly, "heteroaryl" refers to an aryl group containing one or more heteroatoms selected from N, O or S. In a specific embodiment, a "heteroaryl" group in the present invention contains 6 to 30 carbon atoms and has at least one 5-8 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N or S.

In the present invention, the number of the term "substitution" may be one or more < e.g. 2,3,4 or 5 >, and when there are a plurality of "substitutions", the "substitutions" are the same or different.

In the present invention, the position of the term "substituted" may be arbitrary, unless otherwise specified.

It will be appreciated by those skilled in the art that, in accordance with conventional practice used in the art, the groups depicted herein are used in the structural formulae

Means that the corresponding group is linked to other fragments, groups in the compound via this site.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: 1. the metal complex prepared by complexing the chiral phosphine ligand and the transition metal can be used as a catalyst for asymmetric catalytic hydrogenation reaction;

2. the metal complex can efficiently catalyze and synthesize a series of chiral beta-aryl amides with high optical purity (ee value is more than 99%), particularly can asymmetrically catalyze and hydrogenate tetra-substituted enamide compounds, can synthesize chiral amides with high optical purity (ee value can reach more than 60%), has ligand bearing capacity (s/c) of 100,000, is far higher than that of the prior art, and has strong economic practicability.

Drawings

FIG. 1 is a single crystal X-ray diffraction of compound h-1;

FIG. 2 is a single crystal X-ray diffraction of compound h-3.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1

This example was prepared from (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phospho-pentayoke) (1) and its metal complex { (norbornadiene) [ (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phospho-pentayoke)]Rhodium tetrafluoroborate, i.e. Rh (nbd) (1) BF ₄ The preparation of the chiral diphosphine ligand and the metal rhodium complex thereof of the invention are illustrated in detail by way of example (the reaction route is shown as follows):

1. preparation of tert-butyl (hydroxymethyl) (vinyl) phosphinyloxy (a)

A1000 mL four-necked flask was taken, the flask was baked with a baking gun, protected with nitrogen, a thermowell and a low-temperature thermometer were inserted into one port, a mechanical stirring device was inserted into one port, a constant-pressure dropping funnel was installed into one port, and nitrogen gas was substituted 3 to 5 times. Carefully withdraw 10mL of PCl from the syringe ₃ The flask was dropped dropwise into the flask until the analytical balance showed 20g (145.6 mmol,1 equivalent), taken out, protected with nitrogen, dissolved by adding 40mL of THF which had been refluxed with sodium wire for three hours, poured into a four-necked flask, and the flask was rinsed with 15 mL of tetrahydrofuran and transferred into the four-necked flask 3 times.

The apparatus was placed in an ice bath at-50 ℃ and 176.9mL (176.9 mmol,1 eq.) of tert-butylmagnesium chloride was taken up by syringe, injected into a constant pressure dropping funnel and slowly added dropwise. After the dropwise addition, the ice bath device is removed, and the temperature is returned to room temperature. After the temperature is stabilized, the reaction is carried out for 2 hours. By using ³¹ And detecting the reaction by P-NMR, and directly putting the next step without separation if the reaction is finished.

The device was placed in an ice bath at-50 ℃ and 154.9mL (154.9 mmol,1.1 equiv.) of vinyl bromide was removed by syringeAnd (4) dissolving magnesium, injecting into a constant pressure dropping funnel, and slowly dropping. After the dropwise addition, the ice bath device is removed, and the temperature is returned to room temperature. After the temperature is stabilized, the reaction is carried out for 2 hours. By using ³¹ And detecting the reaction by P-NMR, and directly putting the next step without separation if the reaction is finished.

A certain amount of deionized water is taken in a container, then the container is sealed, and nitrogen is injected into the container to remove trace oxygen dissolved in the water. 20mL of deionized water from which peroxide was removed was taken out with a syringe, injected into a constant pressure dropping funnel, and slowly dropped. After the dropwise addition, the device is put into an oil bath kettle at 45 ℃ for reaction for 3h (or at room temperature for 20 h), and the mixture is used ³¹ Detecting the reaction by P-NMR, and directly putting the reaction into the next step without separation if the reaction is finished.

A saturated sodium hydroxide solution containing 29g of NaOH (725mmol, 5 equivalents) and prepared by using deionized water for removing peroxide is introduced into a container, nitrogen is protected, 100mL of formaldehyde solution (1233mmol, 10 equivalents) and the prepared NaOH solution are extracted by a syringe and injected into a constant-pressure dropping funnel, and the mixture is slowly dropped in an ice bath at the temperature of-20 ℃. After the completion of the dropwise addition, the reaction was returned to room temperature, and then the apparatus was placed in an oil bath pan at 50 ℃ for reaction for 3 hours, followed by detection of the reaction by TLC (developing solvent: ethyl acetate/methanol volume ratio 10, color development by potassium permanganate developer) and, if the reaction was completed, post-treatment.

The apparatus was cooled to room temperature, and then the system pH was adjusted to 1 with 2mol/L HCl solution. The organic phase was concentrated by several extractions with ethyl acetate and water. The organic phase was dried with saturated brine and anhydrous sodium sulfate. The organic phase was spin dried. Adding silica gel powder (200-300 meshes) into the organic phase, stirring the mixture, filling the mixture into a column by using pure ethyl acetate, loading the mixture into the column by a dry method, performing column chromatography by using an eluent of 20 volume ratios of ethyl acetate to methanol, and collecting a product to obtain a yellow viscous liquid with the yield of 5.502g and the yield of 27.5%.

a： ¹ H NMR(500MHz,Chloroform-d)δ6.46-6.15(m,3H),4.15-4.10(d, J＝14.4Hz,1H),4.01-3.96(d,J＝14.4Hz,1H),1.19(d,J＝14.5Hz,9H)； ¹³ C NMR (126MHz,Chloroform-d)δ136.99,125.79,57.71,31.53,24.35； ³¹ P NMR(162 MHz,Chloroform-d)δ45.59；ESI-MS:m/z 163.00[M+H]+.

Preparation of 3- (tert-butyl) -2-hydro-1,3-oxyphosphoryl-3-oxo (b)

10g (25mmol, 1 equiv.) of tert-butyl (hydroxymethyl) (vinyl) phosphine oxide was placed in a baked Schlenk tube under nitrogen protection, 8g (2.7 mL) of liquid bromine (50mmol, 2 equiv.) and 50mL of carbon tetrachloride were added, and the mixture was magnetically stirred at 0 ℃ for about 0.5h, then returned to room temperature and reacted for 3h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20, color developed by potassium permanganate developer) and worked up if the reaction was complete. After the reaction was completed, the stirrer was taken out, and a saturated sodium sulfite solution was gradually added dropwise until the orange-red color disappeared. Then, the organic phase is separated, dried by anhydrous sodium sulfate, spin-dried and put into the next step.

4.8g of sodium tert-butoxide (50mmol, 2 eq.) are added and reacted with 50mL of tetrahydrofuran for 40 min. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20, color developed by potassium permanganate developer) and worked up if the reaction was complete. After the reaction is finished, taking out the stirring rod, adding a proper amount of silica gel powder, loading the mixture by a dry method, loading the mixture into a column by ethyl acetate, performing column chromatography by using an eluent with a volume ratio of ethyl acetate to methanol being 80 to obtain a product, concentrating and spin-drying the product to obtain a yellow oily liquid with the yield of 7.5g and 75 percent.

b： ¹ H NMR(500MHz,Chloroform-d)δ7.24-7.19(dd,J＝25.4,4.7Hz, 1H),5.34-5.31(dd,J＝16.75,4.7Hz,1H),4.25(dd,J＝14.4,3.9Hz,1H), 4.16(dd,J＝14.4,10.2Hz,1H),1.16(d,fJ＝16.0Hz,9H)； ¹³ C NMR(126 MHz,Chloroform-d)δ163.89(d,J＝10.4Hz),91.75,91.05,64.39,63.93, 32.25(d,J＝75.4Hz),24.37； ³¹ P NMR(162MHz,Chloroform-d)δ72.56. ESI-MS:m/z 161.0[M+H]+.

Preparation of 3- (tert-butyl) -2-hydro-1,3-oxo, phospho-penta-3-oxo (c)

1g (6.2473mmol, 1 equivalent) of 3- (tert-butyl) -2-hydro-1,3-oxyphosphoryl-3-oxy was placed in a Schlenk tube, 5mL of ethyl acetate and 0.1g of palladium on carbon (10%) were added, hydrogen gas was replaced three times under one atmosphere, and after completion, the mixture was magnetically stirred at an external temperature of 40 ℃ for about 6 hours, and then returned to room temperature. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol at a volume ratio of 20, color developed by potassium permanganate developer) and worked up if the reaction was complete. After the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the mixture by a dry method, loading the mixture into a column by ethyl acetate, performing column chromatography by using an eluent with the volume ratio of ethyl acetate to methanol being 20, collecting a product, concentrating and spin-drying to obtain a yellow oily liquid product with the yield of 0.8904g and the yield of 89%.

c： ¹ H NMR(500MHz,Chloroform-d)δ7.27(s,0H),4.19(ddd,J＝19.2,9.5, 6.8Hz,1H),4.12(dd,J＝13.2,2.6Hz,1H),4.04(tt,J＝10.0,6.5Hz,1H),3.59 (dd,J＝13.2,6.7Hz,1H),1.23(d,J＝15.1Hz,9H)； ¹³ C NMR(126MHz, Chloroform-d)δ68.11,64.19,63.71,31.79,31.28,24.27； ³¹ P NMR(162MHz, Chloroform-d)δ48.63,48.35,48.01,47.73.ESI-MS:m/z 163.05[M+H] ⁺ .

Preparation of 3- (tert-butyl) -2-hydro-1,3-oxo, phospha-penta-3-thioxo (d)

10g (62.473mmol, 1 eq) of 3- (tert-butyl) -2-hydro-1,3-oxo, phospha-penta-3-oxo are placed in a Schlenk tube under nitrogen, 100mL of tetrahydrofuran, 60.8mL of polymethylhydrosiloxane and 25.2mL of tetraisopropyl titanate (87.462mmol, 1.4 eq) are added and reacted at an external temperature of 70 ℃ for 4h. The reaction was checked by TLC (developer: volume ratio of ethyl acetate to methanol 10, color development with potassium permanganate developer) and carried on to the next step if the reaction was complete. After the reaction was completed, the reaction system was cooled to 0 ℃ and 3g of sulfur powder (93.7 mmol,1.5 equivalents) was slowly added dropwise and reacted at 0 ℃ for 1 hour. The reaction is detected by TLC (developing solvent: the volume ratio of petroleum ether to ethyl acetate is 2:1, the color of a potassium permanganate developer is developed), and if the reaction is finished, water is added for quenching the reaction. The mixture was extracted with dichloromethane and water, and the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 20.

d： ¹ H NMR(500MHz,Chloroform-d)δ4.47(d,J＝12.4Hz,1H),4.37– 4.25(m,1H),4.01–3.94(m,1H),3.63(dd,J＝12.4,1.0Hz,1H),2.43(d,J＝10.3 Hz,1H),2.05(d,J＝6.1Hz,1H),1.28(d,J＝16.7Hz,9H)； ¹³ C NMR(126MHz, Chloroform-d)δ77.27,77.02,76.76,70.80,70.44,69.02,33.54,33.19,30.12, 29.70,24.98,24.96； ³¹ P NMR(162MHz,Chloroform-d)δ76.17.ESI-MS:m/z 179.04[M+H] ⁺ .

5.R-3- (tert-butyl) -2-hydro-1,3-oxo, preparation of phosphorus-penta-3-sulfide (e-1)

Using a chiral preparation column AD-H column for separation. The specific method comprises the following steps:

preparation of column type: CHIRALPAK AD-H, particle Size =5 μm; dimensions =4.6mm x 250mm;

mobile phase: isopropanol/n-hexane =5/95, flow rate: 1ml per minute; detection wavelength: 210nm. Retention time: t is t ₁ =7.1min (S configuration), t ₂ =12.3min (R configuration).

Preparation of 6.R-3- (tert-butyl) -2-hydro-1,3-oxo, P-penta-3-oxo (f-1)

1g (5.6mmol, 1 eq) of R-3- (tert-butyl) -2-hydro-1,3-oxo, phospho-pentan-3-thio was placed in a Schlenk tube, 5mL of methanol and 0.3mL of hydrogen peroxide (30%) were added, and the mixture was magnetically stirred at 30 ℃ external temperature for about 6h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20, color developed by potassium permanganate developer) and worked up if the reaction was complete. After the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the sample by a dry method, loading ethyl acetate into a column, and carrying out reaction by using a reaction mixture of ethyl acetate and methanol in a volume ratio of 20:1, performing column chromatography, collecting the product, concentrating and spin-drying to obtain a yellow oily liquid with the yield of 0.86g and 95%.

f-1： ¹ H NMR(500MHz,Chloroform-d)δ4.24-4.10(m,2H),4.12(dd,J＝ 13.2,2.6Hz,1H),4.08-4.01(m,1H),3.59-3.57(dd,J＝13.2,6.7Hz,1H),2.10- 1.86(m,2H),1.24-1.21(d,J＝15.1Hz,9H)； ¹³ C NMR(126MHz,Chloroform-d) δ68.11,64.19,63.71,31.79,31.28,24.27； ³¹ P NMR(162MHz,Chloroform- d)δ48.63,48.35,48.01,47.73.ESI-MS:m/z 163.05[M+H] ⁺ .

Preparation of 7.S-3- (tert-butyl) -2-hydro-1,3-oxo, P-penta-3-borane (g)

5g (30.8mmol, 1 equiv.) of S-3- (tert-butyl) -2-hydro-1,3-oxo, phosphorus-pentan-3-oxo were placed therein under nitrogen, 50mL of THF, 10mL of polymethylhydrosiloxane and 11.6 mL of tetraisopropyl titanate (40mmol, 1.3 equiv.) were added and reacted at an external temperature of 70 ℃ for 4 hours. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 10, color developed by potassium permanganate developer) and the next step was carried out when the reaction was completed. After the reaction was completed, the reaction system was cooled to 0 ℃ and 36.9mL of 1M borane-tetrahydrofuran solution (36.9 mmol,1.2 eq) was slowly added dropwise and reacted at 0 ℃ for 1h at ambient temperature. The reaction was checked by TLC (developing solvent: volume ratio of petroleum ether to ethyl acetate 6:1, color development with potassium permanganate developer), and if the reaction was complete, the reaction was quenched by addition of saturated aqueous sodium hydroxide. The mixture was extracted with dichloromethane, separated, and the organic phase was dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of petroleum ether to ethyl acetate being 50.

g-1： ¹ H NMR(500MHz,Chloroform-d)δ4.43(dd,J＝12.3,3.2Hz,1H), 4.27-4.19(m,1H),3.73-3.66(m,2H),2.10-2.01(m,2H),1.21-1.18(d,J＝15), 0.9-0.21(m,3H)； ¹³ C NMR(126MHz,Chloroform-d)δ69.32,69.29,65.55,65.34, 27.39,27.18,25.55,25.53,22.65,22.38； ³¹ P NMR(162MHz,Chloroform-d)δ 48.18(dd,J＝100.6,45.4Hz).ESI-MS:m/z 163.1[M+H] ⁺ .

8. Preparation of (2R, 2' R,3S,3' S) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospha-penta-yoke) -3,3' -diborane (h-1)

2g (12.3 mmol,1 eq) of S-3- (tert-butyl) -2-hydro-1,3-oxo, phospha-penta-3-borane were placed in a Schlenk tube under nitrogen, and 10mL of THF, 1.4mL of TMEDA (18.5 mmol,1.5 eq) were added. 10.9mL of 1.7M t-butyllithium (18.5 mmol,1.5 equiv.) was added dropwise at 2d/s under magnetic stirring at-78 deg.C for about 15min, after which 4.1g of copper chloride (30.8 mmol,2.5 equiv.) was added while maintaining at-78 deg.C, and the reaction was allowed to resume at room temperature for 45min. The reaction is detected by TLC (developing solvent: petroleum ether and ethyl acetate volume ratio 6:1, potassium permanganate developer color development), and after-treatment is carried out if the reaction is finished. After completion of the reaction, the mixture was extracted with ethyl acetate and a 10% aqueous solution of sodium hydroxide, and the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 100, collecting a product, concentrating and spin-drying to obtain a white solid product, wherein the yield is 0.6g and is 30.6 percent.

h-1： ¹ H NMR(500MHz,Chloroform-d)δ4.39-4.37(dd,2H),4.27-4.24(m, 2H),3.74(m,2H),2.21-2.20(m,2H),2.08-2.07(m,2H),1.25(d,J＝13.9Hz, 18H),0.81-0.25(m,6H)； ¹³ C NMR(101MHz,Chloroform-d)δ73.67,70.12, 28.34,28.08,25.71,22.58,22.26.； ³¹ P NMR(162MHz,Chloroform-d)δ59.04. ESI-MS:m/z 321.21[M+H] ⁺ .

Single crystal X-ray diffraction thereof: space group P21 2, unit cell parameters

α =90 °, β =90 °, γ =90 °, cell volume

The product h-3 was (2R, 2' S,3S,3' S) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospha-pentayoke) -3,3' -diborane: ¹ H NMR(500MHz,Chloroform-d)δ4.39-4.37(dd,1H),4.34- 4.31(m,1H),4.23-4.17(m,2H),4.02-3.95(m,1H),3.74-3.68(m,1H),2.24-2.06 (m,4H),1.29-1.23(dd,18H),0.90-0.21(m,6H)； ³¹ P NMR(162MHz, Chloroform-d)δ60.78,50.14.ESI-MS:m/z 321.21[M+H]+.

single crystal X-ray diffraction thereof: space group P21, cell parameters

α =90 °, β =107.131 (3) °, γ =90 °, unit cell volume

9. Preparation of (2R,2 'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphur-penta-yoke) (1)

100mg (0.31mmol, 1 eq) of (2R, 2' R,3S,3' S) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospho-penta-nyl) -3,3' -diborane were placed in a Schlenk tube under nitrogen, 6mL of toluene, 105mg of 1,4-diazabicyclo [2.2.2] octane (0.94mmol, 3 eq) were added. Magnetic stirring was carried out at an external temperature of 60 ℃ for about 2h. The vacuum pump reduced the pressure to remove most of the toluene solvent. Degassed water (5 mL) was carefully added to the residue. Degassed ether (5 mL) was added to the mixture at room temperature, and after stirring at 60 ℃ for 0.5 hour, the organic phase was separated, dried over sodium sulfate, concentrated, and subjected to anhydrous oxygen-free neutral alumina column chromatography (petroleum ether/ether = 3:1) to give the desired ligand (2r, 2'r,3s, 3's) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-pentayoke) (68 mg, 75%) as a colorless oil.

1： ¹ H NMR(500MHz,Chloroform-d)δ4.79-4.77(d,J＝3.72,2H),4.20-4.17 (m,4H),2.16(m,4H),1.24-1.19(d,J＝15)； ³¹ P NMR(162MHz,Chloroform-d)δ 2.51.ESI-MS:m/z 291.21[M+H] ⁺ .

10. Metal complex { (norbornadiene) [ (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphur-pentayoke)]Rhodium tetrafluoroborates, i.e. Rh (nbd) (1) BF ₄ Preparation of

Bis (norbornadiene) rhodium (I) tetrafluoroborate (18.7 mg,0.05mmol, 1 equiv.) was dissolved in tetrahydrofuran (0.5 mL) under nitrogen, and a solution of ligand (2R, 2'R,3S, 3'S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphorous-pentayoke) (1,16mg, 0.055mmol,1.1 equiv.) in tetrahydrofuran (0.5 mL) was added with stirring at 0 ℃. After the reaction system was stirred at room temperature for 0.5 hour, most of the solvent was removed by vacuum pump concentration under reduced pressure. Degassed diethyl ether (10 mL) was added, and the mixture was stirred for 10 minutes, followed by filtration under nitrogen atmosphere to give the objective compound { (norbornadiene) [ (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphene-pentayoke) as a red solid]Rhodium tetrafluoroborate, i.e. Rh (nbd) (1) BF ₄ (43.4mg, 0.0425mmol,85％)。

Rh(nbd)(1)BF ₄ : ¹ H NMR(400MHz,Chloroform-d)δ6.98(br s,2H),5.26(s, 2H),4.58-4.50(m,2H),4.40-4.38(d,J＝10Hz,2H),2.35(br s,2H),2.17(br s,2H), 1.23-1.21(d,J＝10Hz,18H)； ³¹ P NMR(162MHz,CDCl3)δ92.3-91.3,(d,2J RhP＝160Hz).

Example 2

Preparation of (2S, 3R, 3R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-penta-yoke) (2) and its metal complex { (norbornadiene) [ (2S, 3R, 3R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-penta-yoke) ] } rhodium tetrafluoroborate, rh (nbd) (2) BF4 (the reaction scheme is shown below)

The compound e-2 obtained by preparative separation on the chiral column in the step (5) in example 1 was prepared according to the procedures and conditions in example 1.

Preparation of S-3- (tert-butyl) -2-hydro-1,3-oxo, phospho-penta-3-oxo

1g (5.6 mmol,1 eq.) of S-3- (tert-butyl) -2-hydro-1,3-oxo, phospho-penta-3-thia was placed in a Schlenk tube, 5mL of methanol and 0.3mL of hydrogen peroxide (30%) were added, and the mixture was magnetically stirred at 30 ℃ external temperature for about 6h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20, color developed by potassium permanganate developer) and worked up if the reaction was complete. After the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the sample by a dry method, loading ethyl acetate into a column, and mixing the ethyl acetate and methanol in a volume ratio of 20:1, performing column chromatography, collecting the product, concentrating and spin-drying to obtain a yellow oily liquid with the yield of 0.86g and 95%.

f-2： ¹ H NMR(500MHz,Chloroform-d)δ4.24-4.10(m,2H),4.12(dd,J＝ 13.2,2.6Hz,1H),4.08-4.01(m,1H),3.59-3.57(dd,J＝13.2,6.7Hz,1H),2.10- 1.86(m,2H),1.24-1.21(d,J＝15.1Hz,9H)； ¹³ C NMR(126MHz,Chloroform-d) δ68.11,64.19,63.71,31.79,31.28,24.27； ³¹ P NMR(162MHz,Chloroform- d)δ48.63,48.35,48.01,47.73.ESI-MS:m/z 163.05[M+H] ⁺ .

Preparation of R-3- (tert-butyl) -2-hydro-1,3-oxo, phospha-penta-3-borane

5g (30.8mmol, 1 equiv.) of S-3- (tert-butyl) -2-hydro-1,3-oxo, phosphorus-pentan-3-oxo were placed therein under nitrogen, 50mL of THF, 10mL of polymethylhydrosiloxane and 11.6 mL of tetraisopropyl titanate (40mmol, 1.3 equiv.) were added and reacted at an external temperature of 70 ℃ for 4 hours. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 10, color developed by potassium permanganate developer) and the next step was carried out when the reaction was completed. After the reaction was completed, the reaction system was cooled to 0 ℃ and 36.9mL of a 1M solution of borane in tetrahydrofuran (36.9 mmol,1.2 eq.) was slowly added dropwise and reacted at 0 ℃ for 1h at ambient temperature. Detecting the reaction by TLC (developer: volume ratio of petroleum ether to ethyl acetate 6:1, color development of potassium permanganate color developing agent), and if the reaction is finished, adding saturated aqueous sodium hydroxide solution to quench the reaction. The mixture was extracted with dichloromethane, the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, performing column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 50.

g-2： ¹ H NMR(500MHz,Chloroform-d)δ4.43(dd,J＝12.3,3.2Hz,1H), 4.27-4.19(m,1H),3.73-3.66(m,2H),2.10-2.01(m,2H),1.21-1.18(d,J＝15), 0.9-0.21(m,3H)； ¹³ C NMR(126MHz,Chloroform-d)δ69.32,69.29,65.55,65.34, 27.39,27.18,25.55,25.53,22.65,22.38； ³¹ P NMR(162MHz,Chloroform-d)δ 48.18(dd,J＝100.6,45.4Hz).ESI-MS:m/z 163.1[M+H] ⁺ .

Preparation of (2S,2 ' S,3R,3' R) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospha-penta-yoke) -3,3' -diborane

Under nitrogen, 2g (12.3 mmol,1 eq) of R-3- (tert-butyl) -2-hydro-1,3-oxo, phospho-pentan-3-borane was placed in a Schlenk tube and 10mL of THF, 1.4mL of TMEDA (18.5 mmol,1.5 eq.) were added. 10.9mL of 1.7M t-butyllithium (18.5 mmol,1.5 eq.) were added dropwise at 2d/s magnetically at-78 deg.C for about 15min, after which 4.1g of cupric chloride (30.8 mmol,2.5 eq.) was added while maintaining at-78 deg.C, and the reaction was allowed to resume at room temperature for 45min. The reaction is detected by TLC (developing solvent: petroleum ether and ethyl acetate volume ratio 6:1, potassium permanganate developer color development), and after-treatment is carried out if the reaction is finished. After completion of the reaction, the mixture was extracted with ethyl acetate and a 10% aqueous solution of sodium hydroxide, and the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 100, collecting a product, concentrating and spin-drying to obtain a white solid product, wherein the yield is 0.6g and is 30.6 percent.

h-2： ¹ H NMR(500MHz,Chloroform-d)δ4.39-4.37(dd,2H),4.27-4.24(m, 2H),3.74(m,2H),2.21-2.20(m,2H),2.08-2.07(m,2H),1.25(d,J＝13.9Hz, 18H),0.81-0.25(m,6H)； ¹³ C NMR(101MHz,Chloroform-d)δ73.67,70.12, 28.34,28.08,25.71,22.58,22.26.； ³¹ P NMR(162MHz,Chloroform-d)δ59.04. ESI-MS:m/z 321.21[M+H] ⁺ .

Preparation of (2S,2 'S,3R,3' R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phospha-pentayoke) (2)

100mg (0.31mmol, 1 eq.) of (2S, 2' S,3R,3' R) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospho-penta-nyl) -3,3' -diborane were placed in a Schlenk tube under nitrogen, 6mL of toluene, 105mg of 1,4-diazabicyclo [2.2.2] octane (0.94mmol, 3 eq.) were added. Magnetically stir at 60 ℃ for about 2h. The vacuum pump reduced the pressure to remove most of the toluene solvent. Degassed water (5 mL) was carefully added to the residue. Degassed ether (5 mL) was added to the mixture at room temperature, and after stirring at 60 ℃ for 0.5 hour, the organic phase was separated, dried over sodium sulfate, concentrated, and subjected to anhydrous oxygen-free neutral alumina column chromatography (petroleum ether/ether = 3:1) to give the desired ligand (2s, 2's,3r,3' r) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-pentayoke) (68 mg, 75%) as a colorless oil.

2： ¹ H NMR(500MHz,Chloroform-d)δ4.79-4.77(d,J＝3.72,2H),4.20-4.17 (m,4H),2.16(m,4H),1.24-1.19(d,J＝15)； ³¹ P NMR(162MHz,Chloroform-d)δ 2.51.ESI-MS:m/z 291.21[M+H] ⁺ .

Metal complex { (norbornadiene) [ (2S, 2'S,3R,3' R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphur-pentayoke)]Rhodium tetrafluoroborates, i.e. Rh (nbd) (2) BF ₄ Preparation of

Bis (norbornadiene) rhodium (I) tetrafluoroborate (18.7 mg,0.05mmol, 1 equiv.) was dissolved in tetrahydrofuran (0.5 mL) under nitrogen, and a solution of ligand (2S, 2'S,3R, 3'R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphorous-pentayoke) (1,16mg, 0.055mmol,1.1 equiv.) in tetrahydrofuran (0.5 mL) was added with stirring at 0 ℃. After the reaction system was stirred at room temperature for 0.5 hour, most of the solvent was removed by vacuum pump concentration under reduced pressure. Degassed diethyl ether (10 mL) was added, and the mixture was stirred for 10 minutes, followed by filtration under nitrogen atmosphere to give the objective compound { (norbornadiene) [ (2S, 2'S,3R,3' R) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphene-pentayoke) as a red solid]Rhodium tetrafluoroborates, i.e. Rh (nbd) (2) BF ₄ (43.4mg, 0.0425mmol,85％)。

Rh(nbd)(2)BF ₄ : ¹ H NMR(400MHz,Chloroform-d)δ6.98(br s,2H),5.26(s, 2H),4.58-4.50(m,2H),4.40-4.38(d,J＝10Hz,2H),2.35(br s,2H),2.17(br s,2H), 1.23-1.21(d,J＝10Hz,18H)； ³¹ P NMR(162MHz,CDCl3)δ92.3-91.3,(d,2J RhP＝160Hz).

Example 3

The complex Rh (nbd) (1) BF of chiral metal rhodium with methyl (Z) -2-acetamido-3-phenylacrylate as substrate ₄ As a catalyst, optically active N-acetyl-L-phenylalanine methyl ester (S) was prepared.

The reaction is as follows: methyl (Z) -2-acetylamino-3-phenylacrylate (22mg, 0.1mmol), rh (nbd) (1) BF was put in a glove box under nitrogen atmosphere ₄ (0.24mg, 0.5. Mu. Mol), 0.5mL of anhydrous methylene chloride was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. And (3) venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution by a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product N-acetyl-L-phenylalanine methyl ester by using a chiral AD-H column high-efficiency liquid phase to be 97%.

N-acetyl-L-phenylalanine methyl ester [ (S) -3a ]: white solid (yield > 99%); 97% ee.

The ee value is measured by a chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=15.2min (R), t2=21.8min (S).

¹ H NMR(500MHz,CDCl ₃ )δ7.35,-7.25(m,3H),7.10-7.08(d,J＝10.45, 2H),4.91-4.88(dd,2H),3.74(s,1H),3.13(m,2H),1.99(s,1H).

Example 4

Chiral metal rhodium complex Rh (nbd) (1) BF with (Z) -2-acetamido-3-phenyl acrylic acid as substrate ₄ As a catalyst, optically active N-acetyl-L-phenylalanine (S) -3b was prepared.

The reaction is as follows: (Z) -2-acetylamino-3-phenylacrylic acid (20.5 mg, 0.1mmol), rh (nbd) (1) BF was reacted in a glove box under nitrogen atmosphere ₄ (0.24mg, 0.5. Mu. Mol), 0.5mL of anhydrous methylene chloride was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. And (3) venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution by a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product N-acetyl-L-phenylalanine to be 97% by using a chiral AD-H column high-efficiency liquid phase.

N-acetyl-L-phenylalanine [ (S) -3b ]: white solid (yield > 99%); 98% ee.

The ee value is determined by chiral high-pressure liquid phase; the N-acetyl-L-phenylalanine firstly reacts in the presence of trimethylsilyldiazomethane to generate N-acetyl-L-phenylalanine methyl ester. High-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=15.2min (S), t2=21.8min (R). ¹ H NMR(500MHz,CD ₃ OD)δ7.31-7.15(m,5H),4.67-4.62 (dd,J＝9.12,4.98Hz,1H),3.34(d,J＝0.63Hz,1H)3.22-3.16(dd,J＝13.89,5.04 Hz,1H),2.96-2.89(dd,J＝13.8,9.2Hz,1H),1.89(s,1H)

Example 5

N- (2-methyl-3,4-dihydronaphthalene-1-ene) acetamide is used as a hydrogenation substrate, and a complex Rh (nbd) (1) BF of chiral metal rhodium ₄ As a catalyst, optically active chiral amide (1S, 2S) -3f was prepared.

The reaction is as follows: n- (2-methyl-3,4-dihydronaphthalen-1-yl) acetamide (20.1mg, 0.1mmol), rh (nbd) (1) BF (1) was placed in a glove box under nitrogen atmosphere ₄ (0.24mg, 0.5. Mu. Mol), 0.5mL of anhydrous methylene chloride was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, and hydrogen was charged to 750psi, reacted at 50 ℃ for 12 hours, and then cooled to room temperature. And (3) discharging hydrogen, opening the reaction kettle, filtering the reaction crude product solution by a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product N- ((1S, 2S) -2-methyl-1,2,3,4-tetrahydronaphthalene-1-yl) acetamide by using a chiral AD-H column high performance liquid phase to be 70%.

N- ((1s, 2s) -2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) acetamide white solid (yield > 99%); 70% ee.

The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=8.7min (S), t2=11.8min (R). ¹ H NMR(500MHz,CD ₃ OD)δ7.24-7.00(m,4H),5.60-5.42(br s,1H),5.27-5.22 (dd,J＝9.45,4.2Hz,1H),2.87-2.75(m,2H),2.01(s,3H),1.86-1.45(m,3H),1.03- 1.01(d,J＝6.8Hz,3H)

1H NMR(500MHz,CDCl3)δ7.24-7.00(m,4H),6.11(d,1H,J＝9.3Hz), 5.20-5.18(dd,1H,J＝9.7,4.7Hz),2.87-2.75(m,2H),2.01-1.95(m,1H),1.92(s, 3H),1.71-1.60(m,1H),1.55-1.40(m,1H),0.98(d,3H,J＝6.9Hz)

Example 6

Chiral metal rhodium complex Rh (nbd) (1) BF with 1- (acetylamino) -1-styrene as hydrogenating substrate ₄ Preparation of optically active chiral (S) -N- (1-phenylethyl) acetamide [ (S) -3h as catalyst]。

The reaction is as follows: 1- (acetylamino) -1-styrene (16 mg,0.1 mmol), rh (nbd) (1) BF was placed in a glove box under nitrogen ₄ (0.24mg, 0.5. Mu. Mol), 0.5mL of anhydrous methylene chloride was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. Discharging hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the product (S) -N- (1-phenylethyl) acetamide [ (S) -3H by using a chiral AD-H column high-efficiency liquid phase]The ee value of (2) was 99%.

(S) -N- (1-phenylethyl) acetamide: white solid (yield > 99%); 99% ee.

The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 95/5,210nm, t1=10.1min (S), t2=12.8min (R).

1H NMR(500MHz,CDCl3)δ7.30-7.27(m,5H),6.09(br,1H),5.16-5.04 (m,1H),1.94(s,3H),1.46(d,J＝6.8Hz,3H).

Example 7

1- (acetylamino) -1-styrene is used as a hydrogenation substrate, (2S, 3R,3' R) -3,3' -di-tert-butyl-2,2 ' -di (1,3-oxygen, phosphorus-pentan) is used as a chiral phosphine ligand, rh (nbd) ₂ BF ₄ Preparation of optically active chiral (R) -N- (1-phenylethyl) acetamide [ (R) -3h as metal catalyst]。

The reaction is as follows: under nitrogen atmosphere, 1- (acetylamino) -1 was placed in a glove boxStyrene (16 mg,0.1 mmol), rh (nbd) ₂ BF ₄ (0.24mg, 0.5. Mu. Mol), (2S, 3R,3' R) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospha-pentayoke) (0.15mg, 0.2. Mu. Mol), 0.5mL of anhydrous dichloromethane was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. Venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a millipore filter to remove metal ions, diluting isopropanol, directly measuring the conversion rate and the product (S) -N- (1-phenylethyl) acetamide [ (R) -3H by using a chiral AD-H column high performance liquid phase]The ee value of (2) was 99%.

(S) -N- (1-phenylethyl) acetamide: white solid (yield > 99%); 99% ee.

The ee value is determined by chiral high-pressure liquid phase; high pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate of 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=10.1min (S), t2=12.8min (R). 1H NMR (500MHz, CDCl) ₃ )δ7.36-7.20(m,5H),6.02(br s,1H),5.16- 5.04(m,1H),1.94(s,1H),1.47-1.44(d,J＝11.4Hz,3H).

Example 8

1- (4-bromophenyl) -2-acetamidopropene is used as a hydrogenation substrate, (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-pentayoke) is used as a ligand, and Rh (nbd) ₂ BF ₄ Optically active chiral (S) -1- (4-bromophenyl) -2-acetamido-propane was prepared for the catalyst.

The reaction is as follows: (E) -1- (4-bromophenyl) -2-acetamidopropene (4 g,16.6 mmol), rh (nbd) was charged in a glove box under a nitrogen atmosphere ₂ BF ₄ (0.03mg, 0.1. Mu. Mol), (2R, 2'R,3S, 3'S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxygen, phosphorus-pentalene) (0.03mg, 0.1. Mu. Mol), 24mL of anhydrous methanol was added to the hydrogenation bottle, and the hydrogenation bottle was transferred to the autoclave. Sealing the reaction kettle, replacing hydrogen for three times, filling hydrogen to 300psi, reacting at 25 ℃ for 12 hours, and cooling toAnd (4) room temperature. And (3) releasing hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product (S) -1- (4-bromophenyl) -2-acetamido-propane by using a chiral AD-H column high-efficiency liquid phase to obtain 98%.

(S) -1- (4-bromophenyl) -2-acetamido-propane: white solid (yield > 99%); 98% ee.

The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate: 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=13.4min (S), t2=17.9min (R).

¹ H NMR(400MHz,CDCl3)δ:7.47(d,J＝8Hz,2H),7.21(d,J＝8Hz, 2H),5.84(s,br,1H),5.05-5.12(m,1H),2.00(s,3H),1.47(d,J＝4Hz,3H).

Example 9

2-methylcyclohexenyl 1-acetamide as a hydrogenation substrate, (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -di (1,3-oxo, phosphorus-pentanedin) as a ligand, rh (nbd) ₂ BF ₄ Optically active chiral (1S, 2R) -2-methylcyclohexyl 1-acetamides were prepared for the catalysts.

The reaction is as follows: 2-methylcyclohexenyl 1-acetamide (0.5 g, 3.2mmol), rh (nbd) was added to a glove box under a nitrogen atmosphere ₂ BF ₄ (1mg, 2.4. Mu. Mol), (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phospha-pentayoke) (0.8mg, 2.4. Mu. Mol), 5mL of anhydrous methanol was added to the hydrogenation bottle, and the hydrogenation bottle was transferred to the autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. And (3) venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution by using a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product (1S, 2R) -2-methylcyclohexyl 1-acetamide by using a chiral AD-H column high-performance liquid phase to obtain 68%.

(1S, 2R) -2-methylcyclohexyl 1-acetamide as a white solid (yield > 99%); 68% ee.

The ee value is measured by a chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate: 0.7mL/min, n-hexane/isopropanol: 95/5,210nm, t1=11.2min (1r, 2s), t2=12.1min (1s, 2r).

¹ H NMR(400MHz,CDCl3)δ:5.53(s,1H),4.02-4.07(m,1H),1.99(s, 3H),1.84(m,1H),1.17-1.65(m,8H),0.86(d,J＝7Hz,3H).

Example 10

1,1-dimethyl-2-acetamidopropene as the hydrogenated substrate, (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phosphorus-pentanyl) as the ligand, rh (nbd) ₂ BF ₄ Optically active chiral (S) -1,1-dimethyl-2-acetamido-propane is prepared for the catalyst.

The reaction is as follows: 1,1-dimethyl-2-acetamidopropene (0.3 g, 2.4mmol), rh (nbd) was placed in a glovebox under nitrogen ₂ BF ₄ (0.7 mg, 2.4. Mu. Mol), (2R, 2'R,3S,3' S) -3,3 '-di-tert-butyl-2,2' -bis (1,3-oxo, phospha-pentayoke) (0.7 mg, 2.4. Mu. Mol), 5mL of anhydrous methanol was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. And (3) releasing hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous filter membrane to remove metal ions, diluting the reaction crude product solution with ethyl acetate, and directly measuring the conversion rate and the ee value of the product (S) -1- (4-bromophenyl) -2-acetamido-propane by using a chiral GC-MS (gas chromatography-Mass spectrometer) column to be 60%.

The ee value is measured by a chiral GC-MS column; chemical GC-MS conditions FUSED SILICA Capillary Column, beta DEX ^TM 225,30m*0.25mm*0.25uMfilm thickness. t ₁ (S)＝11.18min，t ₂ (R)＝11.45min. ¹ H NMR(500MHz,CDCl3)δ:5.38(s,1H), 3.82-3.89(m,1H),1.97(s,3H),1.63-1.72(m,1H),1.06(d,J＝6.7Hz,3H),0.89 (d,J＝5.4Hz,3H),0.88(d,J＝6.2Hz,3H).

Example 11

1- (acetamido) -1-styrene is used as hydrogenation substrate, complex Rh (nbd) (1) BF of chiral metal rhodium ₄ Optically active chiral (S) -N- (1-phenylethyl) acetamide ((S) -3 h) was prepared as a catalyst.

The reaction is as follows: 1- (acetylamino) -1-styrene (11 g, 68.2 mmol), rh (nbd) (1) BF was placed in a glove box under nitrogen atmosphere ₄ (0.4 mg, 0.68. Mu. Mol), 110mL of anhydrous methylene chloride was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. Discharging hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the product (S) -N- (1-phenylethyl) acetamide [ (S) -3H by using a chiral AD-H column high-efficiency liquid phase]The ee value of (b) was 99%.

(S) -N- (1-phenylethyl) acetamide white solid (yield > 99%); 99% ee.

The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate: 1mL/min, n-hexane/isopropanol: 95/5,210nm, t1=10.1min (S), t2=12.8min (R).

Comparative example 1

(Z) -2-acetamido-3-phenylacrylic acid is used as a hydrogenation substrate, (2R, 2S,3S,3' S) -3,3' -di-tert-butyl-2,2 ' -di (1,3-oxygen, phosphorus-pentayoke) (compound h-3) is a chiral phosphine ligand, rh (nbd) ₂ BF ₄ Preparation of optically active chiral amides (S) -3b as metal catalysts。

The reaction is as follows: (Z) -2-acetylamino-3-phenylacrylic acid (20.5mg, 0.1mmol), rh (nbd) was added under a nitrogen atmosphere in a glove box ₂ BF ₄ (0.19mg, 0.5. Mu. Mol), (2S, 3R, 3'R) -3,3' -di-tert-butyl-2,2 ' -bis (1,3-oxo, phospha-pentan) (0.15mg, 0.5. Mu. Mol), 0.5mL of anhydrous dichloromethane was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle was closed, hydrogen was replaced three times, hydrogen was charged to 750psi, and after 12 hours of reaction at 50 ℃, cooled to room temperature. And (3) discharging hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product N-acetyl-L-phenylalanine to be 58 percent ee by using a chiral AD-H column high performance liquid phase.

N-acetyl-L-phenylalanine [ (S) -3b ]: white solid (yield > 99%); 58% ee.

The ee value is measured by a chiral high-pressure liquid phase; the N-acetyl-L-phenylalanine firstly reacts in the presence of trimethylsilyldiazomethane to generate N-acetyl-L-phenylalanine methyl ester. High-pressure liquid phase conditions: chiral AD-H column, flow rate 1mL/min at 25 ℃, n-hexane/isopropanol: 95/5,210nm, t1=15.2min (S), t2=21.8min (R). ¹ H NMR(500MHz,CD ₃ OD)δ7.31-7.15(m,5H),4.67- 4.62(dd,J＝9.12,4.98Hz,1H),3.34(d,J＝0.63Hz,1H)3.22-3.16(dd,J＝13.89, 5.04Hz,1H),2.96-2.89(dd,J＝13.8,9.2Hz,1H),1.89(s,1H)。

Comparative example 2

(E) -1- (4-bromophenyl) -2-acetamidopropene is used as a hydrogenation substrate, (2R, 2' R,3R,3' R) -4,4' -di (9-methoxy) -3,3' -di-tert-butyl-2,2 ',3,3' -tetrahydro-2,2 ' -dibenzo [ d][1,3]Oxygen, phosphorus-penta-yokes as ligands, rh (nbd) ₂ BF ₄ Optically active chiral (S) -1- (4-bromophenyl) -2-acetamido-propane is prepared for the catalyst.

The reaction is as follows: under the nitrogen atmosphere, 1- (4-bromophenyl) -2-acetamidopropan is added into a glove boxAlkene (4g, 16.6mmol), rh (nbd) ₂ BF ₄ (0.03mg, 0.1. Mu. Mol), (2R, 2'R,3R,3' R) -4,4 '-bis (9-methoxy) -3,3' -di-tert-butyl-2,2 ',3,3' -tetrahydro-2,2 '-dibenzo [ d, 3' -methyl ester][1,3]Oxygen, phosphorus-Pentamide (0.04 mg, 0.1. Mu. Mol), 24mL of anhydrous methanol was added to the hydrogenation flask, which was transferred to the autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. And (3) releasing hydrogen, opening the reaction kettle, filtering the reaction crude product solution through a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product (S) -1- (4-bromophenyl) -2-acetamido-propane by using a chiral AD-H column high-efficiency liquid phase to obtain 91%.

(S) -1- (4-bromophenyl) -2-acetamido-propane: white solid (yield > 99%); 91% ee.

¹ H NMR(400MHz,CDCl3)δ:1.47(d,J＝4Hz,3H),2.00(s,3H),5.05-5.12 (m,1H),5.84(s,br,1H),7.21(d,J＝8Hz,2H),7.47(d,J＝8Hz,2H).

Comparative example 3

Optically active chiral (1R, 2S) -2-methylcyclohexyl 1-acetamide was prepared using 2-methylcyclohexenyl 1-acetamide as the substrate for hydrogenation and rhodium metal complex { (norbornadiene) [ (2S, 2' S,3S,3' S) -4,4' -bis (9-anthracenyl) -3,3' -di-tert-butyl-2,2 ',3,3' -tetrahydro-2,2 ' -dibenzo [ d ] [1,3] oxy, phospho-penta } tetrafluoroborate as the catalyst.

The reaction is as follows: 2-methylcyclohexenyl 1-acetamide (0.5 g,3.2 mmol), metal complex { (norbornadiene) [ (2S, 2S,3S,3 'S) -4,4' -bis (9-anthracenyl) -3,3 '-di-tert-butyl-2,2', 3,3 '-tetrahydro-2,2' -dibenzo [ d ] [1,3] oxygen, phosphorus-penta-conjugated } rhodium tetrafluoroborate (2.2 mg, 2.4. Mu. Mol), 5mL of anhydrous methanol was added to a hydrogenation bottle under a nitrogen atmosphere, and the hydrogenation bottle was transferred to a high pressure reactor. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. And (3) venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution by using a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product (1R, 2S) -2-methylcyclohexyl 1-acetamide by using a chiral AD-H column high-performance liquid phase to be 20%.

(1S, 2R) -2-methylcyclohexyl 1-acetamide: white solid (yield > 99%); 20% ee.

The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate: 0.7mL/min, n-hexane/isopropanol: 95/5,210nm, t1=11.2min (1r, 2s), t2=12.1min (1s, 2r).

¹ H NMR(400MHz,CDCl3)δ:5.53(s,1H),4.02-4.07(m,1H),1.99(s,3H), 1.84(m,1H),1.17-1.65(m,8H),0.86(d,J＝7Hz,3H).

Comparative example 4

1,1-dimethyl-2-acetamidopropene is used as the hydrogenated substrate, (2R, 2' R,3R,3' R) -4,4' -di (9-methoxy) -3,3' -di-tert-butyl-2,2 ',3,3' -tetrahydro-2,2 ' -dibenzo [ d][1,3]Oxygen, phosphorus-penta-yokes as ligands, rh (nbd) ₂ BF ₄ Optically active chiral (S) -1,1-dimethyl-2-acetamido-propane is prepared for the catalyst.

The reaction is as follows: 1,1-dimethyl-2-acetamidopropene (0.1 g, 0.8mmol), rh (nbd) was placed in a glove box under nitrogen ₂ BF ₄ (2mg, 6. Mu. Mol), (2R, 2' R,3R,3' R) -4,4' -bis (9-methoxy) -3,3' -di-tert-butyl-2,2 ',3,3' -tetrahydro-2,2 ' -dibenzo [ d][1,3]Oxygen, phosphorus-pentayoke (4 mg, 9. Mu. Mol), 5mL of anhydrous methanol was added to the hydrogenation flask, which was transferred to the autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. Discharging hydrogen, opening the reaction kettle, filtering the reaction crude product solution by a microporous filter membrane to remove goldAfter isopropyl alcohol is diluted, the conversion rate and the ee value of the product (S) -1- (4-bromophenyl) -2-acetamido-propane are determined by a chiral AD-H column high performance liquid phase, and the product yield is 8%.

Comparative example 5

Optically active chiral (1R, 2S) -2-methylcyclohexyl 1-acetamide was prepared using 2-methylcyclohexenyl 1-acetamide as a hydrogenation substrate and rhodium tetrafluoroborate as a metal complex { (norbornadiene) [ (2S, 2'S,3R,3' R) -Tangphos ] } as a catalyst.

The reaction is as follows: 2-methylcyclohexenyl 1-acetamide (0.5 g,3.2 mmol), rhodium metal complex { (norbornadiene) [ (2S, 2'S,3R,3' R) -Tangphos ] } rhodium tetrafluoroborate (1.4 mg, 2.4. Mu. Mol), and 5mL of anhydrous methanol were added to a hydrogenation flask under a nitrogen atmosphere in a glove box, and the hydrogenation flask was transferred to an autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction kettle is cooled to the room temperature. And (3) venting hydrogen, opening the reaction kettle, filtering the reaction crude product solution by using a microporous filter membrane to remove metal ions, diluting isopropanol, and directly measuring the conversion rate and the ee value of the product (1R, 2S) -2-methylcyclohexyl 1-acetamide by using a chiral AD-H column high-performance liquid phase to be 53%.

(1r, 2s) -2-methylcyclohexyl 1-acetamide: white solid (11% yield); 53% ee. The ee value is determined by chiral high-pressure liquid phase; high-pressure liquid phase conditions: chiral AD-H column, 25 ℃, flow rate: 0.7mL/min, n-hexane/isopropanol: 95/5,210nm, t1=11.2min (1r, 2s), t2=12.1min (1s, 2r).

Claims

1. A metal complex of formula I:

wherein R is ¹ And R ² Each independently is C ₁ ～C ₁₀ Alkyl groups of (a); m is a group of ⁿ⁺ Is a transition metal ion; the transition metal ion M ⁿ⁺ Is Rh ⁺ (ii) a The carbons marked with x are all chiral carbons with S configuration or all chiral carbons with R configuration;

p marked by x is all S configuration chiral P or all R configuration chiral P;

R ^- is an anion.

2. The metal complex of claim 1, wherein when R is ¹ Or R ² Each independently is C ₁ ～C ₁₀ Alkyl of (2), C ₁ ～C ₁₀ Alkyl of (A) is C _1-6 An alkyl group;

and/or, the anion is BF ₄ ^- 、SbF ₆ ^- 、TfO ^- 、B(C ₆ H ₅ ) ₄ ^- 、B[3,5-(CF ₃ ) ₂ C ₆ H ₃ ] ₄ ^- Or PF ₆ ^- 。

3. The metal complex of claim 2, wherein when R is ¹ Or R ² Each independently is C ₁ ～C ₆ When said alkyl is substituted, said C _1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl;

and/or, the anion is BF ₄ ^- Or PF ₆ ^- ；

And/or, R ¹ And R ² The same;

and/or, the metal complex is

4. A metal complex according to claim 1, wherein the metal complex is any one of the following compounds:

5. a process for preparing a metal complex according to any one of claims 1 to 4, comprising the steps of: in an inert gas atmosphere, in a first organic solvent, carrying out a complexing reaction shown as the following on a transition metal precursor shown as a formula III and a ligand compound shown as a formula II to obtain the metal complex;

6. use of a metal complex according to any one of claims 1 to 4 in an asymmetric catalytic hydrogenation reaction, comprising the steps of: in an organic solvent in the presence of a hydrogen atmosphere and said metal complex

Carrying out asymmetric catalytic hydrogenation reduction reaction on the compound A with the structure to obtain a corresponding compound B;

wherein, when the metal complex is

When the compound B is in the dominant configuration shown as B-1,

when the metal complex is

When the compound B is in the dominant configuration shown as B-2,

7. the use of claim 6, wherein said composition comprises

Compound a of the structure is represented by formula a-1:

wherein the dotted line represents none or annulation;

said R ^d Independently is optionally substituted alkyl or cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

said "optionally substituted" is unsubstituted or substituted with: halogen, haloalkyl, -OH, -CN, alkyl-oxy, alkyl-S-, carboxyl, ester, amide, aminosulfonyl, or phenyl; the number of said "substitution" may not be limited; when optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, said "substitution" is the formation of a ring-union with said cycloalkene, heterocycloalkene, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

8. The use of claim 7, wherein R is ^a 、R ^b Or R ^c When it is an optionally substituted alkyl group, said optionally substituted alkyl group is C ₁ ～C ₁₀ Alkyl groups of (a);

and/or, said R ^a 、R ^b Or R ^c In the case of optionally substituted alkyl-oxy-carbonyl, said optionally substituted alkyl-oxy-carbonyl is C ₁ ～C ₆ Alkyl-oxy-carbonyl of (a);

and/or, said R ^a 、R ^b Or R ^c When the aryl is optionally substituted, the optionally substituted aryl is phenyl or halogen substituted phenyl;

and/or, said "R ^a And R ^b When taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkene, said "optionally substituted cycloalkene" is a benzocyclohexene or cyclohexene;

and/or, said R ^d When it is an optionally substituted alkyl group, said optionally substituted alkyl group is C ₁ ～C ₆ The alkyl group of (1).

9. The use according to claim 8, wherein compound a and correspondingly compound B-1 are selected from the following compounds:

said compound A and correspondingly compound B-2 are selected from the following compounds:

10. a compound II of any one of the following structures: